HBeAg阴性慢性乙型肝炎的阿德福韦酯长期治疗（三）

w****2

Safety

Adverse events during weeks 49 to 96 were similar in severity, nature, and frequency to those during the initial 48-week treatment period. At least one adverse event was reported in 58 of 79 patients (73 percent) in the continued-adefovir group, 41 of 60 patients (68 percent) in the placebo–adefovir group, and 32 of 40 (80 percent) in the adefovir–placebo group. The most common adverse events reported in the continued-adefovir group were headache, abdominal pain, and pharyngitis (Table 4).

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   Table 4. Proportion of Patients with the Most Common Adverse Events and Renal Events.



The study drug was discontinued because of adverse events in two patients in the continued-adefovir group (a protocol-defined increase in serum creatinine levels of 0.5 mg per deciliter [44.2 µmol per liter] and hepatocellular carcinoma) and in three patients in the adefovir–placebo group (jaundice, elevated alanine aminotransferase levels, and a skin disorder).

No notable differences were seen in laboratory values from week 48, with the exception of increases in alanine aminotransferase levels associated with the withdrawal of adefovir dipivoxil therapy. In the adefovir–placebo group, 13 patients (32.5 percent) had alanine aminotransferase levels that were 10 times the upper limit of normal or higher. Elevations of alanine aminotransferase levels were observed in 6 percent of patients who continued to receive adefovir dipivoxil over 96 weeks. No patients had clinical signs of decompensation or required the intervention of an investigator. Of the 13 patients with elevations of alanine aminotransferase levels, 10 had an increase within 12 weeks after the cessation of adefovir dipivoxil therapy.

There were no overall changes in serum creatinine and phosphorus levels. Two patients in the continued-adefovir group had a confirmed increase in serum creatinine levels of 0.5 mg per deciliter or more from baseline. In one case, the highest value remained within the normal range and resolved with continued treatment. In the other case, the highest value was 2.3 mg per deciliter (203.3 µmol per liter), which returned to normal after discontinuation of the study drug. One additional patient in year 3 had a confirmed serum creatinine increase that returned to baseline within eight weeks after the cessation of adefovir dipivoxil. The safety profile over 144 weeks remained consistent with that seen earlier in the study.

Discussion

As shown in other studies, treatment of HBeAg-negative chronic hepatitis B with lamivudine effectively suppresses HBV replication and results in biochemical remission and histologic improvement in more than two thirds of patients.7,8,13 However, relapse has occurred in the majority of HBeAg-negative patients after the cessation of therapy.8,17 Similarly, in this study, when treatment with adefovir dipivoxil was discontinued, the virologic, biochemical, and histologic benefits that had been gained in the first 48 weeks were lost. This finding suggests that because HBsAg seroconversion is rare,2,4,11 long-term therapy will be needed in the majority of patients. Post-treatment flares in serum alanine aminotransferase levels were seen after therapy was stopped. Although these events were self-limiting in this study, it is important to monitor patients carefully after discontinuation of treatment with adefovir dipivoxil.8,18

To ensure a favorable risk–benefit profile, any treatment regimen must provide durable efficacy and limited toxicity, with minimal or no emergence of viral resistance. The development of viral resistance over time with the use of lamivudine, which is associated with a loss of clinical response, is common and may become serious in patients with advanced disease.18 In another study, peginterferon therapy produced a sustained response in terms of normalization of alanine aminotransferase levels for up to 24 weeks after treatment was stopped, and 19 percent of patients had undetectable HBV DNA levels at week 24 of follow-up. However, further follow-up is required to see if this response will be sustained.19

Our study demonstrated that with prolonged therapy, adefovir dipivoxil brought about increasing and persistent virologic, biochemical, and histologic responses, with delayed and infrequent development of resistance. Among patients who began adefovir dipivoxil in the second 48 weeks, undetectable HBV DNA levels and normalization of alanine aminotransferase levels were achieved in a significant proportion of patients. However, comparisons of this subgroup of patients with those treated for 96 weeks should be made cautiously, since differences existed in baseline characteristics at the initiation of treatment with adefovir dipivoxil. Our results also suggest that an additional histologic benefit may occur with extended treatment, whereas cessation of treatment results in a reversal of improvement.

The adverse events associated with extended treatment with adefovir dipivoxil were similar in nature, severity, and frequency to those observed over the previous 48 weeks. Although increases in serum creatinine levels have previously been seen with higher daily doses (>30 mg), the risk is low with a daily dose of 10 mg.

The findings of this study raise two important questions: When should treatment be initiated, and when is it safe to stop? In view of the progressive course of HBeAg-negative chronic hepatitis B1,3 and the progression of liver damage in patients who received placebo for 48 weeks in this study, it is reasonable to suggest that treatment should not be delayed. However, long-term therapy will be needed for the majority of patients. Therefore, there are several important factors to be weighed before treatment is begun: the patient's age, the severity of liver disease, the risk of disease progression, the risk of resistance, the likelihood of compliance, and the costs associated with long-term therapy.

Treatment with adefovir dipivoxil for 144 weeks resulted in continuing benefits in terms of viral suppression, normalization of biochemical measures, and histologic improvement. These benefits were associated with a delayed and infrequent emergence of resistance, making adefovir dipivoxil an excellent candidate for the long-term management of HBeAg-negative chronic hepatitis B.




Supported by Gilead Sciences.

Drs. Xiong, Currie, and Brosgart and Ms. Ma and Ms. Arterburn are employees of Gilead Sciences and report having equity ownership in Gilead Sciences. Drs. Hadziyannis, Heathcote, Marcellin, and Goodman report having received consulting fees from Gilead Sciences. Drs. Hadziyannis and Marcellin report having received lecture fees from Gilead Sciences.

We are indebted to John Fry and Michael Wollman for their assistance in the preparation of the manusc**t.

* Other members of the Adefovir Dipivoxil 438 Study Group are listed in the Appendix.


Source Information

From the Department of Medicine and Hepatology, Henry Dunant Hospital (S.J.H.), and Western Attica General Hospital (N.C.T.) — both in Athens; Toronto Western Hospital, University of Toronto, Toronto (E.J.H.); the Department of Internal Medicine, National Chen Kung University Hospital, Tainan, Taiwan (T.-T.C.); Georgios Papanikolaou Hospital, Thessaloniki, Greece (G.K.); Azienda Ospedaliera San Giovanni Battista, Turin, Italy (M.R.); Service d'Hepatologie, INSERM Unité 481; Centre de Recherche Claude Bernard sur les Hepatites Virales, Hôpital Beaujon, Clichy, France (P.M.); the Division of Gastroenterology, National University Hospital, Singapore (S.G.L.); the Armed Forces Institute of Pathology, Washington, D.C. (Z.G.); and Gilead Sciences, Foster City, Calif. (J.M., S.A., S.X., G.C., C.L.B.).

Address reprint requests to Dr. Hadziyannis at the Department of Medicine, Henry Dunant Hospital, 107 Mesogion Ave., Athens 11526, Greece, or at hadziyannis@ath.forthnet.gr.

水**秀

我们的水平没有这么高啊

随**扬

水平不高，看起来很费力，能不能翻译过来。

水**秀

翻译什么呀,估计他自己也未必看的明白,就是转来勉强拉分而已

w****2

好的，我有空就翻译过来